CTLA-4 is required by CD4+CD25+ Treg to control CD4+ T-cell lymphopenia-induced proliferation

Eur J Immunol. 2009 Jun;39(6):1544-51. doi: 10.1002/eji.200838603.

Abstract

CTLA-4 is constitutively expressed by CD4(+)CD25(+)Foxp3(+) Treg but its precise role in Treg function is not clear. Although blockade of CTLA-4 interferes with Treg function, studies using CTLA-4-deficient Treg have failed to reveal an essential requirement for CTLA-4 in Treg suppression in vivo. Conditional deletion of CTLA-4 in Foxp3(+) T cells disrupts immune homeostasis in vivo but the immune processes disrupted by CTLA-4 deletion have not been determined. We demonstrate that Treg expression of CTLA-4 is essential for Treg control of lymphopenia-induced CD4 T-cell expansion. Despite IL-10 expression, CTLA-4-deficient Treg were unable to control the expansion of CD4(+) target cells in a lymphopenic environment. Moreover, unlike their WT counterparts, CTLA-4-deficient Treg failed to inhibit cytokine production associated with homeostatic expansion and were unable to prevent colitis. Thus, while Treg developing in the absence of CTLA-4 appear to acquire some compensatory suppressive mechanisms in vitro, we identify a non-redundant role for CTLA-4 in Treg function in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD / metabolism
  • Antigens, CD / physiology*
  • Antigens, Surface / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / transplantation
  • CTLA-4 Antigen
  • Cell Proliferation / drug effects
  • Colitis / immunology
  • Colitis / prevention & control
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA-Binding Proteins / genetics
  • Enzyme Inhibitors / pharmacology
  • Immune Tolerance
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Interleukin-2 Receptor alpha Subunit / metabolism*
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology
  • Lymphopenia / genetics
  • Lymphopenia / immunology*
  • Lymphopenia / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Transforming Growth Factor beta / genetics
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Tryptophan / analogs & derivatives
  • Tryptophan / pharmacology

Substances

  • Antigens, CD
  • Antigens, Surface
  • CD223 antigen
  • CTLA-4 Antigen
  • Ctla4 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-2 Receptor alpha Subunit
  • Rag2 protein, mouse
  • Receptors, Transforming Growth Factor beta
  • Tryptophan